ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Ann Thorac Surg 2008;86:1243-1249. doi:10.1016/j.athoracsur.2008.06.043
© 2008 The Society of Thoracic Surgeons
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Chiao-Po Hsu
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsu, C.-P.
Right arrow Articles by Shih, C.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsu, C.-P.
Right arrow Articles by Shih, C.-C.
Related Collections
Right arrow Myocardial infarction
Right arrowRelated Article

Original Articles: Adult Cardiac

Extracellular Matrix Remodeling Attenuated After Experimental Postinfarct Left Ventricular Aneurysm Repair

Chiao-Po Hsu, MDa,b, Chun-Yao Huang, MDc, Jih-Shiuan Wang, MDa, Pi-Chi Sun, MSa, Chun-Che Shih, MD, PhDa,b,*

a Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
b National Yang-Ming University, Institute of Clinical Medicine, School of Medicine, Taipei, Taiwan
c Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan

Accepted for publication June 9, 2008.

* Address correspondence to Dr Shih, Department of Cardiovascular Surgery, Taipei-Veterans General Hospital, No. 201, Sec 2, Shi-Pai Rd, Taipei, 112, Taiwan (ROC) (Email: ccshih{at}vghtpe.gov.tw).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Left ventricular aneurysm repair (LVAR) prevents congestive heart failure after myocardial infarction (MI). LV dilation after MI is related to postinfarct myocardial remodeling and leads to CHF. Because changes in matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and the physical properties of collagens are involved in myocardial remodeling, the effect of postinfarct LVAR on these factors was tested.

Methods: Rats with surgically induced MI, which did or did not receive postinfarct LVAR, were compared with each other and with controls. TIMP messenger RNA and protein expression, MMP gelatin zymography activity, and collagen fibrosis were measured in heart tissue.

Results: A threefold difference in the infarction area ratio was observed between samples of LVAs and of repaired LVAs. Compared with rats without LVAR, rats with repaired LVAs exhibited a higher percentage fractional shortening and significantly lower LV end-systolic and end-diastolic diameters. These salutary effects on LV diameter after LVAR were accompanied by a reversal of myocardial remodeling activity. After MI, TIMP expression decreased, MMP activity increased, and collagen fibrosis increased. After LVAR, TIMP expression increased, and MMP activity and collagen fibrosis decreased. These markers of remodeling activity changed significantly and approached preinfarct levels after LVAR.

Conclusions: This study demonstrated that postinfarct LVAR prevents further congestive heart failure by attenuating myocardial remodeling in the LV and is thus indicated both to prevent heart failure and to reduce excessive postinfarct myocardial remodeling.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Structural alterations to the myocardial extracellular matrix during left ventricular (LV) remodeling constitute a prognostic milestone after acute myocardial infarction (MI) [1, 2]. The dynamic pathologic process precipitates from macrophage phagocytosis of the necrotic myocardium and concomitant myofibroblast and endothelial proliferation into the infarct zone [3, 4]. Granulation tissue, with a provisional matrix enriched with matricellular protein and proteoglycans such as interstitial collagen type IV, laminin, and fibronectin, replaces necrotic tissues until resorption, wherein extensive tissue apoptosis results in a thin hypocellular scar [5, 6]. At the tissue level, interstitial collagen type I and type II fibers interconnect and mediate myocyte and muscle fiber organization, optimizing myocardial force generation and transmission; when such collagen fibrils and struts are lost, myocyte slippage, LV dilation, and ventricular wall thinning may occur, increasing the incidence of aneurysm formation, progressive contractile dysfunction, and death [7, 8].

Such extracellular matrix remodeling requires proteolysis, and a change in the activity of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) during the development of morphologic changes after MI in both infarcted and noninfarcted regions has been demonstrated in both animal models and in humans [4, 9–11]. MMPs comprise a large family of extracellular enzymes that exhibit generic structural features involved in the regulation of proteolytic activity. Clinical and experimental studies have documented modified expression of interstitial collagenase (MMP-1), stromelysin (MMP-3), 72-kDa gelatinase (MMP-2), 92-kDa gelatinase (MMP-9), and TIMP-1 and TIMP-2 during cardiac hypertrophy, remodeling, and failure [5, 6, 12–14]. Direct genetic evidence for a role in cardiac remodeling has been documented for MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-3; MMP-9 and MMP-2 deficient mice, specifically, are more resistant to cardiac rupture and show decreased cardiac dilation subsequent to acute MI [15, 16]. Administration of broad-spectrum MMP inhibitors further attenuates myocardial remodeling in pacing-induced congestive heart failure [12] and in the early period after MI [10].

A recent report demonstrated that left ventricular assist device (LVAD) support might be associated with the expression level of MMPs and TIMPs. MMPs were down-regulated but TIMPs were up-regulated in the failing human heart after support with LVADs, suggesting that mechanical unloading with LVAD attenuates LV remodeling and alters LV plasticity [17]. A large multicenter study also evaluated the results of surgical anterior ventricular endocardial restoration in patients with a dilated, remodelled LV resulting from an anterior infarction [18].

In this study we evaluated the salutary effects of postinfarct LV aneurysm repair (LVAR) on rat myocardial remodeling in relation to TIMP expression, MMP gelatinolytic activity, and collagen fibrosis. We hypothesized that the elimination of dyskinetic areas and the reduction of LV volume would induce modulation of MMPs, which in turn would significantly attenuate the extracellular matrix remodeling process and the dysfunction of the failing heart.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Animals
All experimental procedures were performed by experienced surgeons and cardiologists, in accordance with the Guidelines for Animal Experiments of Veterans General Hospital–Taipei, which conforms to the code of the Guide for the Care and Use of Laboratory Animals in Taiwan.

Seventy-two female Sprague-Dawley rats weighing 190 to 240 g were stratified into three groups after randomization using the unbalanced complete random allocation method due to the higher incidence of death associated with MI: 15 underwent thoracotomy only (group 1, sham operation), 25 with postinfarct LVA underwent rethoracotomy (group 2), and 32 with postinfarct LVA underwent surgical repair (group 3).

Rat Model of MI
Rats underwent ligation of the left anterior descending coronary artery to produce a MI, as described by Pfeffer and colleagues [19]. Briefly, rats were anesthetized with enflurane, intubated, and were ventilated with 1.5% to 2% enflurane in oxygen. A left thoracotomy was performed at the fourth intercostal space, the pericardium was gently ruptured, and the heart was exteriorized. The left anterior descending coronary artery was ligated 2 to 3 mm from its origin about at the level of the tip of the left atrial appendage with a permanent 7-0 polypropylene suture. The heart was returned to the chest, the rib space and overlying muscles were closed, and the lungs were reinflated by positive expiratory pressure.

After recovery from anesthesia and extubation, the rats were returned to their cages. They were given water and standard rat food and housed in a climate-controlled environment with a 12-hour light/dark cycle.

Postinfarct LVA Plication
Two weeks after MI, rats were anesthetized and underwent a second left thoracotomy, during which the heart was carefully dissected free of adhesions to visualize the extent of the LVA. Rats whose MI was not large enough visually were excluded from the study. Large LVA were identified, and the apex of the heart was lifted to obtain a motionless operative field. A purse-string suture was created with 5-0 polypropylene suture (round needle) just onto the borderline between infarcted and intact myocardium so that the infarct zone was excluded. The thoracotomy was closed, and the rats were allowed to recover.

Tissue Preparation
Twelve weeks after the second operation, echocardiographic studies were performed just before the sacrifice as described previously [20] to ensure that infarction area ratio was significantly decreased after aneurysm repair. Then all sham, LVA, and LVAR rats were anesthetized and perfused through the abdominal aorta with a 0.9% saline solution until the blood was removed.

A median sternotomy was performed to expose the heart and great vessels, and the heart was then immediately harvested and placed into ice-cold saline. A longitudinal incision was made along the axis from base to apex, the areas of the MI or plication were excised, and the remaining LV myocardium was stored in liquid nitrogen (–0°C).

For the histologic study, the right atrium was exposed, the ascending aorta was cannulated using a 22-gauve angiocatheter, and then the distal aorta was clamped. High potassium solution 50 mL (5 mL KCl in 500 mL normal saline) was administered at 100 cm H2O through a catheter to arrest the heart in diastole. Next, 50 mL 4% paraformaldehyde was infused through the coronary system to fix the heart at physiologic pressure.

After removal of the atria and great vessels, the right ventricle free wall was excised and the tissue blocks were blotted dry. The right ventricle (free wall) and LV (free wall plus septum) were weighed separately. The LV samples were transversely sectioned into four segments as blocks 1 to 4 from base to apex and fixed in 4% paraformaldehyde in phosphate-buffered saline (pH 7.4), paraffin-embedded, and sectioned.

Measurement of TIMP Expression
Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) for TIMP-1, TIMP-2, TIMP-3, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was performed on prepared RNA isolated from LV tissue as previously described [21]. The following forward (F) and reverse (R) oligonucleotides were used for RT-PCR:

TIMP-1 (499 bp) F: 5'-GCTAGAGCAGATACCACGATGGCG-3'; R: 5'-TGCAAGGGATGGCTGAACAGGG-3';
TIMP-2 (438 bp) F: 5'-GTGAGCGAGAAGGAGGTGGATTCC-3'; R: 5'-CTTGATGCAGGCAAAGAACTTGGC-3';
TIMP-3 (335 bp) F: 5'-CGTGCACATGCTCGCCCAGC-3'; R: 5'-GGCCCTTGCGCTGGGACAG-3'; and
GAPDH (452 bp) F: 5'-ACCACAGTCCATGCCATCAC-3'; R: 5'-TCCACCACCCTGTTGCTGTA-3'.

Immunostaining was performed using the following antibodies: monoclonal anti-TIMP-1 (Calbiochem, San Diego, CA), polyclonal anti-TIMP-2 (Chemicon, Temecula, CA), polyclonal anti-TIMP-3 and anti-TIMP-4 (Chemicon), and monoclonal antitubulin (Sigma, St. Louis, MO). Protein extracts were prepared using NE-PER Nuclear and Cytoplasmic Extraction Reagents (Pierce, Rockford, IL) according to the manufacturer's instructions. Protein concentration was determined using the Coomassie Plus Protein Assay Reagent Kit (Pierce).

The reactions were developed with enhanced chemiluminescence reagents (Amersham, Piscataway, NJ), and images were obtained by exposing x-ray film. The films were digitized and quantified with the ImageQuant (Amersham) software.

Gelatin Zymography
Gelatin zymography was performed as previously described after myocardial extracts were isolated from frozen cardiac samples [21]. Both inactivated and activated extracts were used in the zymography experiments. To activate MMPs, 40 µg frozen protein lysates were thawed on ice and then activated with 7-mg/mL trypsin for 15 minutes. Then trypsin was inhibited by adding 50-mmol/L phenylmethanesulfonyl fluoride (PMSF, Sigma) serine protease inhibitor. Then, 10-mmol/L freshly prepared p-aminophenylmercuric acetate in 50-mmol/L sodium hydroxide was added, and samples were incubated for 1 hour at 37°C. The samples were mixed with Laemmli sample loading buffer without β-mercaptoethanol or boiling.

Lysates were electrophoresed in precast zymogram gels containing 10% gelatin substrate set in the polyacrylamide matrix. After running, the gels were incubated in 1x zymogram renaturing buffer with gentle agitation for 30 minutes at room temperature. The gels were rinsed two times in deionized water for 10 minutes and moved to 1x zymogram developing buffer. The gel was equilibrated for 30 minutes at room temperature with gentle agitation, then incubated with fresh 1x zymogram developing buffer at 37°C for at least 24 hours. After staining with Coomassie Blue R-250 for 30 minutes, gels were destained with destaining solution (methanol/acetic acid/water at 50:10:40) until the lytic bands were optimally contrasted. Gels were dried, scanned, and analyzed by densitometry using Image-Pro Plus software (National Institutes of Health, Bethesda, MD).

Collagen Morphometry
Morphometric analysis was performed as previously described [22] with 4-µm-thick tissue sections. Briefly, 5 random fields obtained from blocks 2 and 4 stained with Masson trichrome were photographed under a microscope (x400). Within each field, segments representing collagen tissue and muscle were identified, and the area of each was calculated by Image-Pro Plus software. The collagen fraction (stained with aniline blue in Masson trichrome) was then calculated for each field as the sum total area of interstitial fibrosis divided by the sum total area of collagen connective tissue plus muscle. Areas of perivascular fibrosis were excluded from this measurement. The operator was blinded to the experimental groups during the analysis.

Statistical Analysis
For statistical analysis, SPSS 10.0 software (SPSS Inc, Chicago, IL) was used. All values are expressed as mean ± standard deviation. Comparison among the three groups was assessed by one-way analysis of variance (ANOVA), followed by the Scheffe post hoc test. A value of p < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Mortality rates of groups 1, 2, and 3 were 0 of 15 (0%), 7 of 25 (28.0%), and 8 of 32 (25.0%), respectively, after the first operation, and 1 of 15 (0.0%), 3 of 18 (16.7%), and 4 of 24 (16.7%), respectively, after the second operation. Of the surviving rats, 2 in group 2 and 3 in group 3 were excluded from the study because their aneurysms were not large enough. Of the remaining 44 rats, 26 were used for the histologic study, and 6 from each group were used for all other evaluations.

TIMPs Messenger RNA Expression
Using RT-PCR (Fig 1), we found that the relative messenger RNA levels of TIMP-1, TIMP-2, and TIMP-3 were lower in group 2 (LVA) and higher in group 3 (LVAR). The nucleotide sequence of rat TIMP-4 was not found in GenBank, therefore TIMP-4 was not analyzed.


Figure 1
View larger version (72K):
[in this window]
[in a new window]

  		Fig 1. Expression of tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, and TIMP-3 messenger RNA in the left ventricle samples measured by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RNA was reverse-transcribed to complimentary DNA and used as the PCR template. Expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control; 35 cycles for TIMPs and 25 cycles for GAPDH. (LVA = left ventricular aneurysm; LVAR = left ventricular aneurysm repair.)

 
TIMPs Protein Expression
The relative protein expression levels of TIMPs were assessed with immunoblots (Fig 2). Expression of TIMP-1 and TIMP-3 was significantly decreased after aneurysm formation (both p < 0.001) and significantly increased after aneurysm repair (p = 0.024 and p = 0.003, respectively). TIMP-2 showed a similar tendency but was not statistically significant (p = 0.223 after LVAR). TIMP-4 expression did not significantly change among the three treatment groups.


Figure 2
View larger version (53K):
[in this window]
[in a new window]

  		Fig 2. Representative immunoblots and relative expression of tissue inhibitor of metalloproteinase (TIMP)-1 (top left), TIMP-2 (top right), TIMP-3 (bottom left), and TIMP-4 (bottom right). Tubulin was used as an internal control. In each group, n = 6; data are presented as the mean ± standard deviation (error bars). (LVA = left ventricular aneurysm; LVAR = left ventricular aneurysm repair.)

 
MMP Activity
To determine whether MMP activity in surviving myocardium changed during aneurysm formation and repair, MMP zymographic gelatinolytic activity was examined from LV myocardial extracts. Both normal and activated samples underwent gelatin zymography. Zymogram lanes containing normal extracts had a lytic band at about 72 kDa (Fig 3, left panel), which is MMP-2. Zymogram lanes containing activated extracts had a lytic band at about 62 to 64 kDa (Fig 3, right panel) that is caused by the mature form of MMP-2, MMP-9, or both. The relative activities of the gelatinolytic bands produced by extracts from the three experimental groups were calculated after densitometric analysis.


Figure 3
View larger version (56K):
[in this window]
[in a new window]

  		Fig 3. Gelatin zymographic activity in left ventricle myocardial extracts was examined. Lanes contain extracts from sham-treated rats (sham), rats with experimentally induced left ventricular aneurysm (LVA), and rats after left ventricular aneurysm repair (LVAR). (Left) When normal rat myocardial extracts are used, a gelatinolytic band is visible at 72 kDa representing a latent form of matrix metalloproteinase (MMP)-2 activity that increases after LVA and decreases after LVAR. (Right) When proteolytically activated rat myocardial extracts are used, a gelatinolytic band is visible at 62 to 64 kDa representing the activity of mature forms of MMPs (either MMP-2, MMP-9, or both) that increases after LVA and decreases after LVAR.

 
The densitometric analysis of the 72 kDa MMP-2 band is shown in Figure 4, left panel. Compared with group 1 (sham operation), gelatinolytic activity increased 2.26 ± 0.57 times (p = 0.008) in group 2 (induced LVA) after LVA formation and only showed an increase of 1.32 ± 0.26 times in group 3 (LVAR) after LVAR. LVA-induced gelatinolytic activity showed a significant decrease (p = 0.010) after LVAR.


Figure 4
View larger version (13K):
[in this window]
[in a new window]

  		Fig 4. The relative gelatinolytic activity of matrix metalloproteinase (MMP) quantitated by densitometry was compared among treatment groups. In each group, n = 6; data are presented as the mean ± standard deviation (error bars). (LVA = left ventricular aneurysm; LVAR = left ventricular aneurysm repair.) (Left) Relative gelatinolytic activity of the latent form of MMP-2. (Right) Relative gelatinolytic activity of mature form MMP (either MMP-2, MMP-9, or both).

 
The densitometric analysis of the 62- to 64-kDa mature MMPs band is shown in Figure 4, right panel. Compared with group 1 (sham operation), gelatinolytic activity in group 2 (induced LVA) increased 1.97 ± 0.59 times (p = 0.004) after LVA formation and only showed an increase of 1.31 ± 0.11 times in group 3 (LVAR) after LVAR. LVA-induced gelatinolytic activity decreased significantly (p = 0.035) after LVAR.

Collagen Morphometry
The rats were sacrificed 12 weeks after the second thoracotomy. Observations of cardiac tissue showed a significant increase in the myocardial interstitial fibrosis among rats with LVA (p = 0.013; Fig 5 and 6A). Go Among the LVAR rats, an improvement was noted in the amount of myocardial interstitial fibrosis (p = 0.025; Fig 5 and 6B).


Figure 5
View larger version (22K):
[in this window]
[in a new window]

  		Fig 5. Myocardial interstitial fibrosis of the left ventricle. Data are expressed as mean ± standard deviation (error bars). (LVA = left ventricular aneurysm; LVAR = left ventricular aneurysm repair.)

 

Figure 6
View larger version (69K):
[in this window]
[in a new window]

  		Fig 6. Representative Masson trichrome stain of (A) left ventricle aneurysm and (B) left ventricle aneurysm repair. (Scale bar = 50 µm.)

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Postinfarct LV remodeling and dilation is a pivotal clinical determinant of morbidity and death [5, 7]. The objectives of LV surgical intervention is to recover LV function by the elimination of dyskinetic areas by restoration of the LV volume (diastolic filling) and by optimization of normal LV intracavity wall tension (systole); both the volume and tension are supported by spherical myocardial fibrils [23]. In the previous report on these rats, echocardiograph data showed statistically significant changes in anterior wall thickness, LV end-systolic and end-diastolic diameters, and fractional shortening; these indicators increase after induced aneurysm and return to normal after aneurysm repair, demonstrating the salutary effects of the aneurysm repair [20].

In this study the left anterior descending coronary artery was ligated artificially to generate an animal model of MI, which then developed a condition comparable to dilated cardiomyopathy. The experimental group received postinfarct LVAR. The result demonstrated that the rat recovered from LV remodeling through postinfarct LVAR, which was closely associated with down-regulation of MMP expression and increased expression of TIMP-1, TIMP-2, and TIMP-3, thereby reducing the deposition of collagen in non-MI myocardium. Differences in TIMP expression within the non-MI myocardium, associated with LV surgical remodeling, implicate that individual TIMPs may be therapeutic targets for the LV restoration process after postinfarct LVA.

Both the three-dimensional structure of the extracellular matrix and its proteolytic remodeling contribute to the cellular microenvironment that mediates cell growth, dimension, motility, differentiation, and survival [6]. MMPs comprise a family of zinc-dependent, extracellular matrix–degrading endopeptidases, each of which has a specific substrate that it degrades and unique interactions with other biomolecules. TIMPs are a family of proteins that are the inhibitors of the MMPs; in dynamic equilibrium with active catalytic MMPs, the TIMP/MMP system contributes to connective tissue extracellular matrix remodeling [11].

Broad-spectrum drugs that inhibit MMP function affect LV remodeling and prevent CHF, albeit with unwanted side effects [10, 11]. Likewise, MMP activity is implicated in modulating LV dilated cardiomyopathy in knockout mice; MMP-9 or MMP-2 knockout mice experience less myocardial remodeling less heart failure after MI [15, 16].

LVAD intervention has also been observed to positively influence recovery from MI and to reduce MMP activity [17]. One hypothesis for why an LVAD device would reduce MMP activity is that MMPs are induced by mechanical stress and strain [6, 12], and when the LVAD reduces the strain on the heart, MMP activity is not stimulated, preventing dilative cardiomyopathy and subsequent heart failure. Such relationships inspired this study to see if LVAR influenced myocardial remodeling in a way similar to LVAD intervention.

Reduction in expression of inhibitory TIMPs as well as stimulation of MMP expression and activation may have contributed to the observed increase in collagen fibrosis seen after the experimental MI in this study. LVAR reversed these effects and may have done so by reducing mechanical strain on the heart, thus preventing the acceleration of myocardial remodeling that could lead to dilative cardiomyopathy.

The findings of this study show that postinfarct LVAR promotes recovery from LV remodeling by returning MMP and TIMP levels toward preinfarct levels. This study further suggests that other therapeutic strategies that can modulate MMP and TIMP levels may also have salutary affects on LVA healing.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The assistance of Ching-ya Hsu is greatly appreciated. This work was supported by grants from the National Science Council, Taiwan SC-95-2341-B-010-028-MY3 and 94-2314-B-010-057; Taipei Veterans General Hospital, Taiwan V95C1-049, V95E1-010, V95ED1-008, V95-S22-005; and Research Foundation of Cardiovascular Medicine (94-01-007), Taipei, Taiwan.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Kostuk WJ, Kazamias TM, Gander MP, Simon AL, Ross J. Left ventricular size after acute myocardial infarction: serial changes and their prognostic significance Circulation 1973;47:1174-1179.[Abstract/Free Full Text]
  2. White HD, Norris RM, Brown MA, Brandt PWT, Whitelock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction Circulation 1987;76:44-51.[Abstract/Free Full Text]
  3. Bing RJ. Myocardial ischemia and infarction: growth of ideas Cardiovasc Res 2001;51:13-20.[Abstract/Free Full Text]
  4. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction Cardiovasc Res 2002;53:31-47.[Abstract/Free Full Text]
  5. Takemura G, Ohno M, Hayakawa Y, et al. Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction Circ Res 1998;82:1130-1138.[Abstract/Free Full Text]
  6. Ross RS. The extracellular connections: the role of integrins in myocardial remodeling J Card Fail 2002;8:S326-S331.[Medline]
  7. Lutgens E, Daemen MJ, de Muinck ED, Debets J, Leenders P, Smits JF. Chronic myocardial infarction in the mouse: cardiac structural and functional changes Cardiovasc Res 1999;41:586-593.[Abstract/Free Full Text]
  8. Braunwald E, Pfeffer MA. Ventricular enlargement and remodeling following acute myocardial infarction: mechanisms and management Am J Cardiol 1991;68:1D-6D.[Medline]
  9. Tyagi SC, Ratajska A, Weber KT. Myocardial matrix metalloproteinase(s): localization and activation Mol Cell Biochem 1993;126:49-59.[Medline]
  10. Rohde LE, Ducharme A, Arroyo LH, et al. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice Circulation 1999;99:3063-3070.[Abstract/Free Full Text]
  11. Heymans S, Luttun A, Nuyens D, et al. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure Nat Med 1999;5:1135-1142.[Medline]
  12. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time-dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function Circ Res 1998;82:482-495.[Abstract/Free Full Text]
  13. Li YY, McTiernan CF, Feldman AM. Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling Cardiovasc Res 2000;46:214-224.[Abstract/Free Full Text]
  14. Reinhardt D, Sigusch HH, Hensse J, Tyagi SC, Korfer R, Figulla HR. Cardiac remodeling in end stage heart failure: upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP Heart 2002;88:525-530.[Abstract/Free Full Text]
  15. Ducharme A, Frantz S, Aikawa M, et al. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction J Clin Invest 2000;106:55-62.[Medline]
  16. Hayashidani S, Tsutsui H, Ikeuchi M, et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction Am J Physiol 2003;285:H1229-H1235.
  17. Li YY, Feng Y, McTiernan CF, et al. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices Circulation 2001;104:1147-1152.[Abstract/Free Full Text]
  18. Athanasuleas CL, Stanley Jr AW, Buckberg GD, et al. Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle after anterior myocardial infarction. RESTORE group. Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol 2001;37:1199-1209.[Abstract/Free Full Text]
  19. Pfeffer MA, Pfeffer JM, Fishbein MC, et al. Myocardial infarct size and ventricular function in rats Circ Res 1979;44:503-512.[Abstract/Free Full Text]
  20. Hsu CP, Huang CY, Wang JS, Chiang HI, Shih CC. Down-Regulation of Apoptosis After Left Ventricular Aneurysm Repair Ann Thorac Surg 2007;84:1279-1287.[Abstract/Free Full Text]
  21. Tyagi SC, Matsubara L, Weber KT. Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus Clin Biochem 1993;26:191-198.[Medline]
  22. Tomita H, Egashira K, Ohara Y, et al. Early induction of transforming growth factor-β via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats Hypertension 1998;32:273-279.[Abstract/Free Full Text]
  23. Kesler KA, Fiore AC, Naunheim KS, et al. Anterior wall left ventricular aneurysm repair. A comparison of linear versus circular closure. J Thorac Cardiovasc Surg 1992;103:841-848.[Abstract]

Related Article

Invited Commentary
Torsten Doenst
Ann. Thorac. Surg. 2008 86: 1249. [Extract] [Full Text] [PDF]



This article has been cited by other articles:


Home page
 Ann. Thorac. Surg.Home page
T. Doenst
Invited Commentary
Ann. Thorac. Surg., October 1, 2008; 86(4): 1249 - 1249.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Chiao-Po Hsu
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hsu, C.-P.
Right arrow Articles by Shih, C.-C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hsu, C.-P.
Right arrow Articles by Shih, C.-C.
Related Collections
Right arrow Myocardial infarction
Right arrowRelated Article

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS